The long-term goal of the proposed work is to increase our understanding of the mechanisms for how the brain is impaired in Type 2 Diabetes Mellitus (T2DM) and insulin resistance (IR). During the first five years of this project we found that individuals with T2DM (as well as those with IR) have specific memory impairments and hippocampal volume reductions that are independent of age and overall brain atrophy but that are related to the degree of impairment of glucose control. Recent literature has uniformly reported that there are reductions in cerebral vascular reactivity in T2DM. Our findings during the current funding period, coupled with these deficits in cerebral vascular reactivity, have led us to develop a testable model that links the two phenomena. We will test whether cerebral vascular reactivity explains the memory deficits and hippocampal volume reductions. Towards this goal we will measure cognition (including memory and frontal lobe measures of performance) with standard neuropsychological tests, hippocampal volumes with validated and reliable MRI- based methods, and cerebral vascular reactivity measured with MRI-based and trans-cranial Doppler (TCD) methods to determine cerebral blood flow at rest and under conditions of increased respiratory CO2. The MRI- based method of blood flow we will use has been recently validated. We hypothesize that our measures of cerebral vascular reactivity will predict our measures of memory and hippocampal volumes. In addition, we will also test whether frontal lobe is an alternative site of T2DM effects, and thus explore the anatomic specificity of our findings. We will also ascertain how inflammatory markers, which are known to be associated with T2DM, insulin resistance, and micro-vessel disease, modify the hypothesized associations between hippocampal integrity and cerebral vascular reactivity. To accomplish these objectives, we will study 150 individuals 45-60 years of age, 50% female, separated into three groups of 50 (T2DM, insulin resistant individuals with normal glucose tolerance, and insulin sensitive controls) matched on age, gender, education, and race. Participants with T2DM will have no evidence of extensive micro-vessel disease and will have never been treated with insulin or insulin secretagogues. We hypothesize that cerebral vascular reactivity will be directly associated with insulin sensitivity. Insulin sensitivity will be computed using the MINMOD approach with data derived from a FSIVGTT. We have the infrastructure and the scientific team in place to successfully carry out the proposed study. We will use standardized and validated techniques for our data acquisition. We have considerable experience in conducting these types of studies. By demonstrating a mechanism by which the brain is affected in T2DM, this study will create the rationale for the use of pharmacological targets to improve cerebral blood flow and vascular reactivity as well as decrease inflammation as a way of protecting the brain of mid-life individuals with T2DM and IR. PUBLIC HEALTH RELEVANCE: Due to the rampant obesity epidemic, type 2 diabetes is also increasing at an alarming rate in the USA. In addition to the ill effects of diabetes on the eyes, kidneys, and limbs, there is now evidence that the brain is also affected early in the disease. The goal of this research is to increase our understanding of how the brain is affected so as to be in a position to develop treatment strategies to try to protect the brain during diabetes.